Boosting T-cell immunity as a therapeutic approach for neurodegenerative conditions: the role of innate immunity.

Our research group has been working for more than a decade on the cross-talk between the immune and the nervous systems. Due to the unique nature of the central nervous system (CNS) as an immune privileged site, it was commonly believed that the nervous system functions optimally without any immune intervention, and that any immune cell infiltration to the CNS is a sign of pathology. However, since the immune system constitutes the body's major defense and repair mechanism, it seemed unreasonable that the CNS would have completely lost the need for assistance from this system. This insight prompted us to revisit the entire question of whether immune cells are required for recovery from CNS injuries. We subsequently made numerous fundamental observations that led us to formulate a unified theory linking all neurodegenerative conditions; thus, we suggested that "T-cell immunity to self maintains the self," at least in the CNS. According to this view, immunity to self ("protective autoimmunity") provides a pivotal role in maintenance, protection, and repair of the healthy and diseased CNS. We further showed that the T cells mediate their effect, at least under pathological conditions, by controlling the recruitment of blood-borne monocytes, which play a crucial local role that cannot be replaced by the resident microglia. Boosting of such a T cell response specific for brain proteins, while carefully choosing the antigen, the carrier, timing, dosing, and regimen should be considered as a way of augmenting a physiological repair mechanism needed to ameliorate disease conditions while restoring equilibrium needed for protection, repair and renewal; such therapy is not intended to modify a single mediator of a single disease, but rather, would serve as an approach for adjusting the levels of the immune response needed to restore a lost balance.

A high-spin ground-state donor-acceptor conjugated polymer.

Interest in high-spin organic materials is driven by opportunities to enable far-reaching fundamental science and develop technologies that integrate light element spin, magnetic, and quantum functionalities. Although extensively studied, the intrinsic instability of these materials complicates synthesis and precludes an understanding of how fundamental properties associated with the nature of the chemical bond and electron pairing in organic materials systems manifest in practical applications. Here, we demonstrate a conjugated polymer semiconductor, based on alternating cyclopentadithiophene and thiadiazoloquinoxaline units, that is a ground-state triplet in its neutral form. Electron paramagnetic resonance and magnetic susceptibility measurements are consistent with a high-to-low spin energy gap of 9.30 × 10-3 kcal mol-1. The strongly correlated electronic structure, very narrow bandgap, intramolecular ferromagnetic coupling, high electrical conductivity, solution processability, and robust stability open access to a broad variety of technologically relevant applications once thought of as beyond the current scope of organic semiconductors.

Direct observation of individual hydrogen atoms at trapping sites in a ferritic steel.

The design of atomic-scale microstructural traps to limit the diffusion of hydrogen is one key strategy in the development of hydrogen-embrittlement-resistant materials. In the case of bearing steels, an effective trapping mechanism may be the incorporation of finely dispersed V-Mo-Nb carbides in a ferrite matrix. First, we charged a ferritic steel with deuterium by means of electrolytic loading to achieve a high hydrogen concentration. We then immobilized it in the microstructure with a cryogenic transfer protocol before atom probe tomography (APT) analysis. Using APT, we show trapping of hydrogen within the core of these carbides with quantitative composition profiles. Furthermore, with this method the experiment can be feasibly replicated in any APT-equipped laboratory by using a simple cold chain.

Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies.

Notch receptors have been implicated as oncogenic drivers in several cancers, the most notable example being NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL). To characterize the role of activated NOTCH3 in cancer, we generated an antibody that detects the neo-epitope created upon gamma-secretase cleavage of NOTCH3 to release its intracellular domain (ICD3), and sequenced the negative regulatory region (NRR) and PEST (proline, glutamate, serine, threonine) domain coding regions of NOTCH3 in a panel of cell lines. We also characterize NOTCH3 tumor-associated mutations that result in activation of signaling and report new inhibitory antibodies. We determined the structural basis for receptor inhibition by obtaining the first co-crystal structure of a NOTCH3 antibody with the NRR protein and defined two distinct epitopes for NRR antibodies. The antibodies exhibit potent anti-leukemic activity in cell lines and tumor xenografts harboring NOTCH3 activating mutations. Screening of primary T-ALL samples reveals that 2 of 40 tumors examined show active NOTCH3 signaling. We also identified evidence of NOTCH3 activation in 12 of 24 patient-derived orthotopic xenograft models, 2 of which exhibit activation of NOTCH3 without activation of NOTCH1. Our studies provide additional insights into NOTCH3 activation and offer a path forward for identification of cancers that are likely to respond to therapy with NOTCH3 selective inhibitory antibodies.

Use of mental health and substance abuse treatment services among adults with HIV in the United States.

BACKGROUND: The need for mental health and substance abuse services is great among those with human immunodeficiency virus (HIV), but little information is available on services used by this population or on individual factors associated with access to care. METHODS: Data are from the HIV Cost and Services Utilization Study, a national probability survey of 2864 HIV-infected adults receiving medical care in the United States in 1996. We estimated 6-month use of services for mental health and substance abuse problems and examined socioeconomic, HIV illness, and regional factors associated with use. RESULTS: We estimated that 61.4% of 231 400 adults under care for HIV used mental health or substance abuse services: 1.8% had hospitalizations, 3.4% received residential substance abuse treatment, 26.0% made individual mental health specialty visits, 15.2% had group mental health treatment, 40.3% discussed emotional problems with medical providers, 29.6% took psychotherapeutic medications, 5.6% received outpatient substance abuse treatment, and 12.4% participated in substance abuse self-help groups. Socioeconomic factors commonly associated with poorer access to health services predicted lower likelihood of using mental health outpatient care, but greater likelihood of receiving substance abuse treatment services. Those with less severe HIV illness were less likely to access services. Persons living in the Northeast were more likely to receive services. CONCLUSIONS: The magnitude of mental health and substance abuse care provided to those with known HIV infection is substantial, and challenges to providers should be recognized. Inequalities in access to care are evident, but differ among general medical, specialty mental health, and substance abuse treatment sectors.

Psychiatric disorders and drug use among human immunodeficiency virus-infected adults in the United States.

BACKGROUND: There have been no previous nationally representative estimates of the prevalence of mental disorders and drug use among adults receiving care for human immunodeficiency virus (HIV) disease in the United States. It is also not known which clinical and sociodemographic factors are associated with these disorders. SUBJECTS AND METHODS: We enrolled a nationally representative probability sample of 2864 adults receiving care for HIV in the United States in 1996. Participants were administered a brief structured psychiatric instrument that screened for psychiatric disorders (major depression, dysthymia, generalized anxiety disorders, and panic attacks) and drug use during the previous 12 months. Sociodemographic and clinical factors associated with screening positive for any psychiatric disorder and drug dependence were examined in multivariate logistic regression analyses. RESULTS: Nearly half of the sample screened positive for a psychiatric disorder, nearly 40% reported using an illicit drug other than marijuana, and more than 12% screened positive for drug dependence during the previous 12 months. Factors independently associated with screening positive for a psychiatric disorder included number of HIV-related symptoms, illicit drug use, drug dependence, heavy alcohol use, and being unemployed or disabled. Factors independently associated with screening positive for drug dependence included having many HIV-related symptoms, being younger, being heterosexual, having frequent heavy alcohol use, and screening positive for a psychiatric disorder. CONCLUSIONS: Many people infected with HIV may also have psychiatric and/or drug dependence disorders. Clinicians may need to actively identify those at risk and work with policymakers to ensure the availability of appropriate care for these treatable disorders.

Quantification of oxide particle composition in model oxide dispersion strengthened steel alloys.

Oxide dispersion strengthened ferritic steels (ODS) are being considered for structural components of future designs of fission and fusion reactors because of their impressive high-temperature mechanical properties and resistance to radiation damage, both of which arise from the nanoscale oxide particles they contain. Because of the critical importance of these nanoscale phases, significant research activity has been dedicated to analysing their precise size, shape and composition (Odette et al., Annu. Rev. Mater. Res. 38 (2008) 471-503 [1]; Miller et al., Mater. Sci. Technol. 29(10) (2013) 1174-1178 [2]). As part of a project to develop new fuel cladding alloys in India, model ODS alloys have been produced with the compositions, Fe-0.3Y2O3, Fe-0.2Ti-0.3Y2O3 and Fe-14Cr-0.2Ti-0.3Y2O3. The oxide particles in these three model alloys have been studied by APT in their as-received state and following ion irradiation (as a proxy for neutron irradiation) at various temperatures. In order to adequately quantify the composition of the oxide clusters, several difficulties must be managed, including issues relating to the chemical identification (ranging and variable peak-overlaps); trajectory aberrations and chemical structure; and particle sizing. This paper presents how these issues can be addressed by the application of bespoke data analysis tools and correlative microscopy. A discussion follows concerning the achievable precision in these measurements, with reference to the fundamental limiting factors.

Nephrogenic diabetes insipidus due to demethylchlortetracycline hydrochloride in a child.

Nephrogenic diabetes insipidus occurred in a 7-year-old child who had received a high dose of demethylchlortetracycline hydrochloride (DMC). The patient had a relatively elevated urinary sodium concentration in addition to isosthenuria. The nephrogenic diabetes insipidus was completely reversible within one month after cessation of DMC administration.

Interstitial deletion of 10q: clinical features and literature review.

We report on a patient with interstitial deletion of 10q and compare her to 8 previously described patients, 2 of whom have chromosomal breakpoints similar to our patient. Minor anomalies including broad forehead, hypertelorism, strabismus, prominent philtrum, and "dysplastic" pinnae are present in our patient. Psychomotor retardation and hypotonia are universal findings in 10q interstitial deletion. Growth retardation, not present in our patient, is seen in some. These clinical findings are sufficiently distinct to suggest early chromosome studies.

Renal and systemic hemodynamics in borderline hypertension.

Cardiac output (CO), renal blood flow (RBF), and glomerular filtration rate were measured in 29 young patients with borderline hypertension, in comparison with 26 normotensive controls of the same age and sex. In patients with borderline hypertension, both CO and RBF were significantly increased, whereas the RBF/CO ratio remained within the normal range. No significant changes in glomerular filtration rate and renal filtration fraction were observed. The study clearly demonstrated that renal ischemia was absent in young patients with borderline hypertension.

The co-occurrence of correct and incorrect HIV transmission knowledge and perceived risk for HIV among women of childbearing age in El Salvador.

This article examines the co-occurrence of correct and incorrect knowledge about documented and undocumented modes of HIV transmission among women of childbearing age in El Salvador, and the relationship between HIV transmission knowledge and perceived risk. Incorrect beliefs about HIV transmission co-occur at high levels with, and are largely independent of, accurate knowledge about documented modes of transmission. The co-occurrence of correct and incorrect HIV transmission knowledge was shown to have important implications for perceived risk. Both correct and incorrect HIV transmission knowledge increased the odds of risk perception; uncertainty about risk was decreased among those with higher levels of correct knowledge and increased among those with higher levels of incorrect knowledge. Among those who considered themselves to be at some risk for HIV, higher levels of correct knowledge reduced uncertainty about the degree of risk, while higher levels of incorrect knowledge increased the degree of risk perceived. High levels of endorsement of the documented modes of HIV transmission do not necessarily indicate accurate or adequate knowledge about HIV transmission in the population. Co-occurring inaccurate beliefs about undocumented modes of transmission reflect cultural understandings of contagion and disease, and influence how individuals make sense of medical-scientific information about transmission. Our results suggest that the co-occurrence of correct and incorrect HIV transmission knowledge shapes individual-level risk perceptions. Given the independence of accurate knowledge and inaccurate beliefs. HIV/AIDS education and prevention programs must seek to directly undermine inaccurate beliefs about HIV transmission as part of their efforts to promote behavior change.

The physical costs of AIDS caregiving.

Informal care has become an increasingly important element in the delivery of health and social services to people living with HIV disease or AIDS (PWAs), yet the provision of such care does not come without costs to the caregiver. Instead, caregiving imposes burdens that may compromise caregiver health. Common ailments among AIDS caregivers were examined with two waves of data from a diverse sample of informal care providers in Los Angeles and San Francisco (N = 642). Symptoms of poor physical health are markedly present among AIDS caregivers and are significantly associated with care-related demands and stressors. This stress and health relationship varies significantly between caregivers who are HIV seropositive and those who are seronegative. Care-related effects are more direct among seronegative caregivers who are perhaps less overwhelmed with the maintenance of their own health. For all caregivers studied, level of depression and prior physical health are strong correlates of these physical ailments. Implications of these results are discussed.

Palatal extension of middle meatal antrostomy.

The palatine bone is an important posterior landmark in the performance of ethmoidectomy. This usually unrecognized structure forms the posterior one third of the lateral nasal wall. Resection of a portion of the palatine bone completes the marsupialization of the sphenoethmoidal recess and medial maxilla. It is a major landmark for localization of the sphenopalatine artery at its entrance into the nose. Middle meatal antrostomy is enhanced by removal of the part of the palatine bone that forms the posterior medial wall of the maxillary sinus. In 1110 consecutive sphenoethmoidectomies, marsupialization of the maxillary sinuses has included partial removal of the perpendicular plate of the palatine bone. Patency has been maintained in all of these antrostomies. Pertinent anatomy and surgical technique are reviewed.

Amenable to reason: Aristotle's rhetoric and the moral psychology of practical ethics.

An Aristotelian conception of practical ethics can be derived from the account of practical reasoning that Aristotle articulates in is Rhetoric and this has important implications for the way we understand the nature and limits of practical ethics. an important feature of this conception of practical ethics is its responsiveness to the complex ways in which agents form and maintain moral commitments, and this has important implications for the debate concerning methods of ethics in applied ethics. In particular, this feature enables us to understand casuistry, narrative, and principlism as mutually supportive modes of moral inquiry, rather than divergent and mutually exclusive methods of ethics. As a result, an Aristotelian conception of practical ethics clears the conceptual common ground upon which practical ethicists can forge a stable and realistic self-understanding.

[Effect of furosemide and ACTH on plasma renin, aldosterone and cortisol levels in normal man]. / Actions du furosémide et de l'ACTH sur l'activité rénine, l'aldostérone et le cortisol plasmatiques chez le sujet normal

Plasma renin activity (PRA), aldosterone and cortisol's variations are studied in normal salt repleted voluntary men (120 mEq/24 h sodium) before and after furosemide infusion and/or constant infusion of ACTH (beta 1-24 corticotrophin). PRA is determined by angiotensin I radioimmunoassay, plasma aldosterone by specific radioimmunoassay and plasma cortisol by competitive transcortine binding radioassay. 1) PRA and plasma aldosterone increase clearly after acute sodium depletion secundary to furosemide infusion; plasma cortisol increases a little. PRA and aldosterone's variations are identical after endogenous ACTH suppression by dexamethazone administration before study. 2) PRA is not influenced by constant infusion (16 ng/kg/mn) after acute infusion (0.3 mg intravenously) of ACTH (beta 1-24); plasma aldosterone and plasma cortisol increase dramatically and remain constant along the experience. 3) If acute sodium depletion is realized 120 mn after ACTH infusion, PRA still raises; on the other hand plasma aldosterone remains constant. These results confirm that acute sodium depletion stimulates aldosterone secretion by the way of renin angiotensin system then ACTH acts directly on the adrenal cortex. Nevertheless the stimulative action of acute sodium depletion on aldosterone secretion is suppressed by previous acute ACTH stimulation.

[Proceedings: Role of endogenous and exogenous ACTH on aldosterone secretion (author's transl)]. / Rôle de l'ACTH endogène sur la sécrétion d'aldostérone

The role of ACTH in the control of aldosterone secretion has been investigated in volunteers under a normal sodium diet. Endogenous ACTH suppression by dexamethasone (DXM) does not alter the plasma aldosterone (PA) response to 20 mg furosemide since identical PA increases are observed in control subjects and in subjects with DXM suppressed endogenous ACTH. The sodium depletion induced by furosemide during continuous ACTH infusion increases plasma renin activity but does not change PA.

Cardiopulmonary blood volume and plasma renin activity in man: preliminary report.

Cardiopulmonary blood volume (CPBV) and plasma renin activity (PRA) were measured simultaneously in five normal subjects and six patients with essential hypertension studied in the following different conditions: supine position, head-down tilt, thigh-cuffs inflation. In each individual, a significant negative correlation (r > or = 0.95) was observed between CPBV and PRA. The slope of the relationship (delta PRA/delta CPBV) was used as an index of sensitivity of the neural control of renin release through cardiopulmonary receptors of the low pressure system. Simultaneously, the sensitivity index of the high pressure baroreflex system (HPB) was evaluated using bolus injections of phenylephrine. In normal subjects and patients with hypertension, the delta PRA/delta CPBV ratio and HBP were strongly correlated. Both indices were negatively correlated to age. It is suggested that the sensitivity of the neural control of renin release as well as the arterial baroreflex sensitivity are influenced by age, and possibly the inflexibility of the vascular system.

Ultrafast electron diffraction pattern simulations using GPU technology. Applications to lattice vibrations.

Graphical processing units (GPUs) offer a cost-effective and powerful means to enhance the processing power of computers. Here we show how GPUs can greatly increase the speed of electron diffraction pattern simulations by the implementation of a novel method to generate the phase grating used in multislice calculations. The increase in speed is especially apparent when using large supercell arrays and we illustrate the benefits of fast encoding the transmission function representing the atomic potentials through the simulation of thermal diffuse scattering in silicon brought about by specific vibrational modes.

Mechanism of efavirenz influence on methadone pharmacokinetics and pharmacodynamics.

Mechanisms by which efavirenz diminishes methadone plasma concentrations are unknown. This investigation determined efavirenz influence on clinical methadone disposition and miosis, intravenous and oral alfentanil clearance (hepatic and intestinal cytochrome P450 3A4/5 (CYP3A4/5) activity), fexofenadine disposition (intestinal transporters activity), and efavirenz clearance and 8-hydroxylation (CYP2B6 activity), and human hepatocyte effects. Efavirenz induced systemic and oral alfentanil clearances two- to fivefold and induced efavirenz 8-hydroxylation. Efavirenz stereoselectively decreased methadone plasma concentrations 50-70%. Methadone systemic and oral clearances, hepatic clearance and extraction ratio, N-demethylation, and metabolite formation clearance were stereoselectively increased two- to threefold. Bioavailability decreased. Efavirenz shifted methadone concentration-miosis curves leftward and upward. Efavirenz induced hepatocyte CYP2B6 and CYP3A4 expression, activity, and methadone N-demethylation. Results show that efavirenz coinduced hepatic CYP2B6 and CYP3A4/5, coinduced hepatic and intestinal CYP3A4/5, and coinduced gastrointestinal CYP3A4/5 and efflux transporters. Methadone disposition was most consistent with efavirenz induction of hepatic CYP2B6-mediated methadone N-demethylation. Efavirenz may alter methadone pharmacodynamics.